1. Field of the Invention
The present invention relates generally to compositions and methods to promote heavy metal detoxification in mammals in need. More specifically, the invention relates to the use of spent hops, zinc, (1,7-Bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione), and (3-(2-(Decahydro-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenenaphthyl)ethylidene)dihydro-4-hydroxyfuran-2(3H)-one) or combinations thereof for heavy metal detoxification in the non-acute state.
2. Description of the Related Art
There are numerous metals which may pose health concerns due to residential or occupational exposure. Of these; antimony, arsenic, bismuth, cadmium, cerium, chromium, cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium, thallium, tin, uranium, vanadium, and zinc are considered the most problematic. Many of these elements are common to our diet and environment and are actually necessary for maintaining good health. However, exposure to larger amounts may result in acute or chronic toxicity.
Heavy metal toxicity can result in damaged or reduced mental and central nervous function, lower energy levels, and damage to blood components, lungs, kidneys, liver, and other vital organs. Furthermore, long term chronic exposure has been attributed to physical, neurological or muscular degenerative processes which appear to mimic muscular dystrophy, multiple sclerosis or Parkinson's or Alzheimer's diseases. Additionally, some heavy metals have been identified as potent mutagens and/or carcinogens.
Heavy metal toxicity symptomology is not difficult to recognize. The symptoms, usually severe, are commonly associated with a known exposure or ingestion of the metal. Onset of symptoms is usually rapid and can include cramping, nausea, and vomiting; pain; sweating; headaches; difficulty breathing; impaired cognitive, motor, and language skills; mania; and convulsions.
Symptoms of chronic exposure are very similar to symptoms of other health conditions and often develop slowly over months or even years. However, the symptoms of toxicity resulting from chronic exposure (impaired cognitive, motor, and language skills; learning difficulties; nervousness and emotional instability; and insomnia, nausea, lethargy, and feeling ill) while easily recognized are much more difficult to associate with their cause. A further problem in identifying chronic exposure occurs because the symptoms of chronic exposure may abate from time to time, leading the afflicted individual to postpone seeking treatment, believing the symptoms are related to something other than metal toxicity.
The most commonly encountered toxic metals include aluminum, arsenic, cadmium, iron, lead, and mercury. Arsenic and lead poisonings tend to be the most common due to their wide use in smelting processes, chemical and glass manufacture, or pesticide use (arsenic) while lead exposure can occur from pipes, paint, batteries, and PVC plastics. Target organs for arsenic toxicity include blood, kidneys and digestive, skin and central nervous systems while lead most commonly targets bones, brain, blood, kidneys and the thyroid.
Cadmium toxicity usually targets the brain and kidney resulting from environmental exposures from PVC pipes, batteries and paint pigments.
Aluminum, although not a “heavy” metal per se, has been associated with neurotoxicity (Halatek T, et al., J Environ Sci Health A Tox Hazard Subst Environ Eng. 43(2):118-24, 2008), Alzheimer's disease (Prolo P., et al., Bioinformation. 2007 2(1):24-7, 2007), Molloy, D W., et al., J Toxicol Environ Health A. 70(23):2011-9, 2007), and cell death (Satoh E., et al., Biol Pharm Bull. 30(8):1390-4, 2007).
Some heavy metals have been identified as potent mutagens and/or carcinogens. These metals have been implicated in apoptosis and cell growth regulation, nuclear transcription regulation and effecting various signal transduction pathways. These metals have also been identified as possessing activity effecting gene expression, carcinogenesis, mutagenesis, and cytotoxicity, as well as in free radical generation. For a review, see Wang S. and Shi X., Mol Cell Biochem 222; 3-9, 2001.
Xenobiotic metabolizing enzymes play a major role in regulating the toxic, oxidative damaging, mutagenic, and neoplastic effects of chemical carcinogens. Mounting evidence has indicated that the induction of phase II detoxification enzymes, such as glutathione S-transferases (GSTs), and NADPH quinone reductase (NQO1) activity result in protection against toxicity and chemical carcinogenesis, especially during the initiation phase. NQO1 is a flavoprotein that catalyzes two electron reduction of quinones and nitrogen oxides (Riley, R. J. and P. Workman, Biochem Pharmacol, 43(8): 1657-69, 1992 and Ross, D., et al., Cancer Metastasis Rev, 12(2): 83-101, 1993). Although the major function of this protein may be to reduce the formation of reactive oxygen species by decreasing one electron reduction and the associated redox cycling, it also plays a role in activation of some anticancer drugs and cancer prevention (Begleiter, A., et al., Cancer Lett, 45(3): 173-6, 1989 and Begleiter, A., et al., Oncol Res, 9(6-7): 371-82, 1997) Recent studies suggest that NQO1 may also be involved in regulation of the transcription factor p53 and apoptosis (Asher, G., et al., Proc Natl Acad Sci USA, 98(3): 1188-93, 2001 and Long, D. J., 2nd, et al., Cancer Res, 62(11): 3030-6, 2002).
The transcriptional activation of the phase II enzymes has been traced to a cis-acting transcriptional enhancer called ARE (Rushmore, T. H., et al., Proc Natl Acad Sci USA, 87(10): 3826-30, 1990), or alternatively, the electrophile response element (Friling, R. S., et al., Proc Natl Acad Sci USA, 87(16): 6258-62, 1990). It has been shown that the transcription factor Nrf-2 positively regulates the ARE-mediated expression of the phase II detoxification enzyme genes. Itoh et al. (Biochem Biophys Res Commun, 236(2): 313-22, 1997) have recently established by gene-targeted disruption in mice that Nrf-2 is a general regulator of the phase II enzyme genes in response to electrophiles and reactive oxygens. More recently, the general regulatory mechanism underlying the electrophile counterattack response has been demonstrated in which electrophilic agents alter the interaction of Nrf-2 with its repressor protein (Keap-1), thereby liberating Nrf-2 activity from repression by Keap-1, culminating in the induction of the phase II enzyme genes and antioxidative stress protein genes via AREs (Itoh, K., et al., Genes Dev, 13(1): 76-86, 1999).
It has been suggested that the dissociation of Nrf-2 from Keap-1 may involve modification of either one of these proteins and could be achieved by direct or indirect mechanisms. For example, Nrf-2 can be phosphorylated by components of the MAP kinase cascade (Yu, R., et al., J Biol Chem, 274(39): 27545-52, 1999), which could result in its dissociation. On the other hand, Dinkova-Kostova et al. (Dinkova-Kostova, A. T., et al., Proc Natl Acad Sci USA, 98(6): 3404-9, 2001) have provided an alternative possibility that the dissociation of this complex may be potentiated by the direct interaction of electrophilic agents with reactive thiol residues in either of the two proteins. This hypothesis is supported by the strong relationship between the potency of the agents as inducers of the gene expression through the ARE and their rate of reaction with sulthydryl groups. This mechanism implies that the inducing agent will become covalently bound either to Keap-1 or Nrf-2.
Heme oxygenase-1 (HO-1) an essential enzyme in heme catabolism, and metallothionein IIA (MT-2A), a small metal-binding protein with clusters of cysteins, are induced in HeLa cells following the treatment with cadmium or zinc. Both proteins are considered to be involved in the defense system against metal toxicity. Heme oxygenase is regulated by both Nrf-2 and MTF-1 transcriptional factors through the activation of ARE and MRE binding sites on heme oxygenase gene.
By and large, medical research has been directed to acute instances of metal toxin exposure where detoxification and removal of the toxic substance must be accomplished rapidly insofar as the continued presence of the metal toxin places the patient in a true life or death situation. The most common detoxification treatments for metal toxicity include chemical inactivation, metabolic detoxification, or, for example, chelation.
Currently, these treatments are considered neither appropriate nor indicated for low level toxin exposures, thereby creating a pressing need for safe and effective methods to detoxify individuals with sub-acute metal toxin exposures before toxin build up reaches the requisite level necessitating the more extreme measures described above. The inventors have identified a number of compounds having a history of safety which modulate the activity of key detoxification enzymes and promote toxin removal from the body. The invention described herein teaches enhancement or inducement of detoxification enzyme systems for sub-acute toxin exposures through modulation of key detoxification enzymes and concomitant administration of additional detoxifying and nutritional agents